DESCRIPTION (Verbatim from Applicant's Abstract): Ischemia/reperfusion induced myocardial injury continues to occur following cardiac operations that have been performed in a technically adequate manner, despite meticulous adherence to presently known principles of myocardial protection. We and others have shown that ischemia/reperfusion injury is exacerbated in the aged heart, with the aged heart exhibiting greater dysfunction as compared to the mature heart. At least two morphologically distinct pathways contribute to ischemia/reperfusion injury, namely necrosis and apoptosis, which may differentially contribute to cell death. Whether these pathways are discriminant or represent a continuum of overlapping biochemical and molecular events and their relative contribution in the aged as compared to the mature heart is unknown. Using a model of stunning and ischemia/reperfusion injury we will investigate the subcellular localization (cytosol, nucleus and mitochondria) of these biochemical events in the in situ blood perfused regional ischemic and cardiopulmonary bypass models to elucidate the contribution of caspase activated apoptosis and DNA replication/repair. Using human atrial cardiomyocyte cell cultures, the role of Ca2+, K+, Na+, pH on pro- and anti-apoptotic proteins and mitochondrial transmembrane potential (+m) will lead to the understanding of the genesis of irreversible injury. We anticipate identifying specific regulatory events and initiation origins to allow for specific and directed intracellular myoprotection [eg. caspase inhibition, heat shock protein induction, K-ATP channel agonists, Na+/H+ antiporter, Na+/Ca2+ channel agonists or antagonists, modulators of mitochondrial transmembrane potential (Tm)] to significantly reduce morbidity and mortality related to cardiac surgery in the elderly.